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SUMMARYThis guidance presents recommendations for clinical microbiology laboratories for processing respiratory samples from people with cystic fibrosis (pwCF). Appropriate processing of respiratory samples is crucial to detect bacterial and fungal pathogens, guide treatment, monitor the epidemiology of cystic fibrosis (CF) pathogens, and assess therapeutic interventions. Thanks to CF transmembrane conductance regulator modulator therapy, the health of pwCF has improved, but as a result, fewer pwCF spontaneously expectorate sputum. Thus, the collection of sputum samples has decreased, while the collection of other types of respiratory samples such as oropharyngeal and bronchoalveolar lavage samples has increased. To optimize the detection of microorganisms, including Pseudomonas aeruginosa, Staphylococcus aureus, Haemophilus influenzae, and Burkholderia cepacia complex; other less common non-lactose fermenting Gram-negative bacilli, e.g., Stenotrophomonas maltophilia, Inquilinus, Achromobacter, Ralstonia, and Pandoraea species; and yeasts and filamentous fungi, non-selective and selective culture media are recommended for all types of respiratory samples, including samples obtained from pwCF after lung transplantation. There are no consensus recommendations for laboratory practices to detect, characterize, and report small colony variants (SCVs) of S. aureus, although studies are ongoing to address the potential clinical impact of SCVs. Accurate identification of less common Gram-negative bacilli, e.g., S. maltophilia, Inquilinus, Achromobacter, Ralstonia, and Pandoraea species, as well as yeasts and filamentous fungi, is recommended to understand their epidemiology and clinical importance in pwCF. However, conventional biochemical tests and automated platforms may not accurately identify CF pathogens. MALDI-TOF MS provides excellent genus-level identification, but databases may lack representation of CF pathogens to the species-level. Thus, DNA sequence analysis should be routinely available to laboratories for selected clinical circumstances. Antimicrobial susceptibility testing (AST) is not recommended for every routine surveillance culture obtained from pwCF, although selective AST may be helpful, e.g., for unusual pathogens or exacerbations unresponsive to initial therapy. While this guidance reflects current care paradigms for pwCF, recommendations will continue to evolve as CF research expands the evidence base for laboratory practices.
ABSTRACT
Cystic fibrosis (CF) airways are L-arginine deficient which may affect susceptibility to infection with certain pathogens. The potential impact of L-arginine supplementation on Pseudomonas aeruginosa, a common CF airway pathogen, is unclear. This study investigated the effects of L-arginine on P. aeruginosa biofilm cultures, using the laboratory strain PAO1 and multi-drug resistant CF clinical isolates. P. aeruginosa biofilms were grown in a chambered cover-glass slide model for 24 h, then exposed to either L-arginine alone or combined with tobramycin for an additional 24 h. Biofilms were visualized using confocal microscopy, and viable cells were measured via plating for colony-forming units. Increasing concentrations of L-arginine in bacterial culture medium reduced the biovolume of P. aeruginosa in a dose-dependent manner. Notably, L-arginine concentrations within the physiological range (50 mM and 100 mM) in combination with tobramycin promoted biofilm growth, while higher concentrations (600 mM and 1200 mM) inhibited growth. These findings demonstrate the potential of L-arginine as an adjuvant therapy to inhaled tobramycin in treating P. aeruginosa infections in people with CF.
Subject(s)
Anti-Bacterial Agents , Arginine , Biofilms , Cystic Fibrosis , Pseudomonas aeruginosa , Tobramycin , Biofilms/drug effects , Biofilms/growth & development , Pseudomonas aeruginosa/drug effects , Arginine/pharmacology , Cystic Fibrosis/microbiology , Cystic Fibrosis/drug therapy , Tobramycin/pharmacology , Anti-Bacterial Agents/pharmacology , Humans , Microbial Sensitivity Tests , Pseudomonas Infections/drug therapy , Pseudomonas Infections/microbiology , Drug Resistance, Multiple, Bacterial/drug effectsABSTRACT
QUESTION: Pseudomonas aeruginosa (Pa) is a common pathogen that contributes to progressive lung disease in Cystic Fibrosis (CF). Genetic factors other than CF-causing CFTR variations contribute approximately 85% of the variation in chronic Pa infection age in CF according to twin studies, but the susceptibility loci remain unknown. Our objective is to advance understanding of the genetic basis of host susceptibility to Pa infection. MATERIALS AND METHODS: We conducted a genome-wide association study (GWAS) of chronic Pa infection age in 1037 Canadians with CF. We subsequently assessed the genetic correlation between chronic Pa infection age and lung function through polygenic risk score (PRS) analysis and inferred their causal relationship through bi-directional Mendelian Randomization analysis. RESULTS: Two novel genome-wide significant loci with lead SNPs rs62369766 (chr5p12; p-value= 1.98 ×10-8) and rs927553 (chr13q12.12; p-value= 1.91 × 10-8) were associated with chronic Pa infection age. The rs62369766 locus was validated using an independent French cohort (N=501). Furthermore, PRS constructed from CF lung function-associated SNPs was significantly associated with chronic Pa infection age (p-value=0.002). Finally, our analysis presented evidence for a causal effect of lung function on the chronic Pa infection age (Beta=0.782â years, p-value= 4.24 × 10-4). In the reverse direction, we observed a moderate effect (Beta=0.002, p-value=0.012). CONCLUSIONS: We identified two novel loci that are associated with chronic Pa infection age in individuals with CF. Additionally, we provided evidence of common genetic contributors and a potential causal relationship between Pa infection susceptibility and lung function in CF. Therapeutics targeting these genetic factors may delay the onset of chronic infections which accounts for significant remaining morbidity in CF.
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BACKGROUND: Elevated markers of systemic and pulmonary inflammation are associated with failure to recover lung function following pulmonary exacerbations in people with cystic fibrosis (pwCF). Our aim was to determine whether adjuvant oral prednisone treatment would improve recovery of forced expiratory volume in 1â s (FEV1) % pred in CF pulmonary exacerbations not responding to antibiotic therapy. METHODS: This was a randomised, double-blind, placebo-controlled trial in pwCF treated with intravenous antibiotics for a pulmonary exacerbation. At day 7, those who had not returned to >90% baseline FEV1 % pred were randomised to adjuvant prednisone 1â mg·kg-1 twice daily (maximum 60â mg·day-1) or placebo for 7â days. The primary outcome was the difference in proportion of subjects who recovered >90% baseline FEV1 % pred at day 14 of i.v. antibiotic therapy. RESULTS: 173 subjects were enrolled, with 76 randomised. 50% of subjects in the prednisone group recovered baseline FEV1 on day 14 compared with 39% of subjects in the placebo group (difference of 11%, 95% CI -11-34%; p=0.34). The mean±sd change in FEV1 % pred from day 7 to day 14 was 6.8±8.8% predicted in the prednisone group and 4.6±6.9% predicted in the placebo group (mean difference 2.2% predicted, 95% CI -1.5-5.9%; p=0.24). Time to subsequent exacerbation was not prolonged in prednisone-treated subjects (hazard ratio 0.83, 95% CI 0.45-1.53; p=0.54). CONCLUSIONS: This study failed to detect a difference in FEV1 % pred recovery between adjuvant oral prednisone and placebo treatment in pwCF not responding at day 7 of i.v. antibiotic therapy for pulmonary exacerbations.
Subject(s)
Anti-Bacterial Agents , Cystic Fibrosis , Prednisone , Humans , Cystic Fibrosis/drug therapy , Cystic Fibrosis/physiopathology , Cystic Fibrosis/complications , Male , Female , Prednisone/administration & dosage , Prednisone/therapeutic use , Double-Blind Method , Anti-Bacterial Agents/administration & dosage , Anti-Bacterial Agents/therapeutic use , Forced Expiratory Volume , Administration, Oral , Adult , Young Adult , Adolescent , Disease Progression , Treatment Outcome , Lung/physiopathology , Lung/drug effectsABSTRACT
Chronic Pseudomonas aeruginosa (Pa) lung infections are the leading cause of mortality among cystic fibrosis (CF) patients; therefore, the eradication of new-onset Pa lung infections is an important therapeutic goal that can have long-term health benefits. The use of early antibiotic eradication therapy (AET) has been shown to clear the majority of new-onset Pa infections, and it is hoped that identifying the underlying basis for AET failure will further improve treatment outcomes. Here we generated machine learning models to predict AET outcomes based on pathogen genomic data. We used a nested cross validation design, population structure control, and recursive feature selection to improve model performance and showed that incorporating population structure control was crucial for improving model interpretation and generalizability. Our best model, controlling for population structure and using only 30 recursively selected features, had an area under the curve of 0.87 for a holdout test dataset. The top-ranked features were generally associated with motility, adhesion, and biofilm formation.
Subject(s)
Cystic Fibrosis , Pseudomonas Infections , Humans , Child , Cystic Fibrosis/complications , Cystic Fibrosis/drug therapy , Pseudomonas aeruginosa , Cell Aggregation , Pseudomonas Infections/complications , Pseudomonas Infections/drug therapy , Lung , Anti-Bacterial Agents/therapeutic useABSTRACT
BACKGROUND: The limits of reproducibility of the lung clearance index (LCI) are higher in children with cystic fibrosis (CF) compared with healthy children, and it is currently unclear what defines a clinically meaningful change. METHODS: In a prospective multisite observational study of children with CF and healthy controls (HCs), we measured LCI, FEV1% predicted and symptom scores at quarterly visits over 2 years. Two reviewers performed a detailed review of visits to evaluate the frequency that between visit LCI changes outside ±10%, ±15%, ±20% represented a clinically relevant signal. In the setting of acute respiratory symptoms, we used a generalised estimating equation model, with a logit link function to determine the ability of LCI worsening at different thresholds to predict failure of lung function recovery at follow-up. RESULTS: Clinically relevant LCI changes outside ±10%, ±15% and ±20% were observed at 25.7%, 15.0% and 8.3% of CF visits (n=744), respectively. The proportions of LCI changes categorised as noise, reflecting biological variability, were comparable between CF and HC at the 10% (CF 9.9% vs HC 13.0%), 15% (CF 4.3% vs HC 3.1%) and 20% (CF 2.4% vs HC 1.0%) thresholds. Compared with symptomatic CF visits without a worsening in LCI, events with ≥10% LCI increase were more likely to fail to recover baseline LCI at follow-up. CONCLUSION: The limits of reproducibility of the LCI in healthy children can be used to detect clinically relevant changes and thus inform clinical care in children with CF.
Subject(s)
Cystic Fibrosis , Humans , Child , Prospective Studies , Reproducibility of Results , Forced Expiratory Volume , LungABSTRACT
BACKGROUND: Antibiotics, such as inhaled tobramycin, are used to eradicate new-onset Pseudomonas aeruginosa (PA) infections in patients with cystic fibrosis (CF) but frequently fail due to reasons poorly understood. We hypothesized that PA isolates' resistance to neutrophil antibacterial functions was associated with failed eradication in patients harboring those strains. METHODS: We analyzed all PA isolates from a cohort of 39 CF children with new-onset PA infections undergoing tobramycin eradication therapy, where 30 patients had eradicated and 9 patients had persistent infection. We characterized several bacterial phenotypes and measured the isolates' susceptibility to neutrophil antibacterial functions using in vitro assays of phagocytosis and intracellular bacterial killing. RESULTS: PA isolates from persistent infections were more resistant to neutrophil functions, with lower phagocytosis and intracellular bacterial killing compared to those from eradicated infections. In multivariable analyses, in vitro neutrophil responses were positively associated with twitching motility, and negatively with mucoidy. In vitro neutrophil phagocytosis was a predictor of persistent infection following tobramycin even after adjustment for clinical risk factors. CONCLUSIONS: PA isolates from new-onset CF infection show strain-specific susceptibility to neutrophil antibacterial functions, and infection with PA isolates resistant to neutrophil phagocytosis is an independent risk factor for failed tobramycin eradication.
Subject(s)
Cystic Fibrosis , Pseudomonas Infections , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/therapeutic use , Cystic Fibrosis/complications , Cystic Fibrosis/microbiology , Humans , Neutrophils , Pseudomonas Infections/microbiology , Pseudomonas aeruginosa/genetics , Tobramycin/pharmacology , Tobramycin/therapeutic useABSTRACT
Treatment of primary ciliary dyskinesia pulmonary exacerbations resulted in an increase in sputum nitric oxide (NO) metabolites and decrease in neutrophilic inflammation. The association between the 2 suggests that neutrophilic inflammation contributes to airway NO deficiency in primary ciliary dyskinesia and that reducing inflammation may lead to improved airway NO homeostasis. TRIAL REGISTRY: ClinicalTrials.gov: NCT01155115.
Subject(s)
Ciliary Motility Disorders , Nitric Oxide , Child , Humans , Inflammation , Lung , Nitric Oxide/metabolism , ThoraxABSTRACT
Rationale: The lung clearance index (LCI) is responsive to acute respiratory events in preschool children with cystic fibrosis (CF), but its utility to identify and manage these events in school-age children with CF is not well defined.Objectives: To describe changes in LCI with acute respiratory events in school-age children with CF.Methods: In a multisite prospective observational study, the LCI and FEV1 were measured quarterly and during acute respiratory events. Linear regression was used to compare relative changes in LCI and FEV1% predicted at acute respiratory events. Logistic regression was used to compare the odds of a significant worsening in LCI and FEV1% predicted at acute respiratory events. Generalized estimating equation models were used to account for repeated events in the same subject.Measurements and Main Results: A total of 98 children with CF were followed for 2 years. There were 265 acute respiratory events. Relative to a stable baseline measure, LCI (+8.9%; 95% confidence interval, 6.5 to 11.3) and FEV1% predicted (-6.6%; 95% confidence interval, -8.3 to -5.0) worsened with acute respiratory events. A greater proportion of events had a worsening in LCI compared with a decline in FEV1% predicted (41.7% vs. 30.0%; P = 0.012); 53.9% of events were associated with worsening in LCI or FEV1. Neither LCI nor FEV1 recovered to baseline values at the next follow-up visit.Conclusions: In school-age children with CF, the LCI is a sensitive measure to assess lung function worsening with acute respiratory events and incomplete recovery at follow-up. In combination, the LCI and FEV1 capture a higher proportion of events with functional impairment.
Subject(s)
Cystic Fibrosis/complications , Cystic Fibrosis/physiopathology , Forced Expiratory Volume/physiology , Lung Diseases/etiology , Lung Diseases/therapy , Adolescent , Child , Female , Humans , Indiana , Male , Ontario , Prospective Studies , Respiratory Function TestsABSTRACT
BACKGROUND: We previously identified Pseudomonas aeruginosa isolates with characteristics typical of chronic infection in some early infections in children with cystic fibrosis (CF), suggesting that these isolates may have been acquired from other patients. Our objective was to define the extent of P. aeruginosa strain-sharing in early CF infections and its impact on antibiotic eradication treatment failure rates. METHODS: We performed whole genome sequencing on isolates from early pediatric CF pulmonary infections and from the following comparator groups in the same hospital: chronic CF infection, sink drains, sterile site infections, and asymptomatic carriage. Univariate logistic regression was used to assess factors associated with treatment failure. RESULTS: In this retrospective, observational study, 1029 isolates were sequenced. The CF clones strain B and clone C were present. In 70 CF patients with early infections, 14 shared strains infected 29 (41%) patients over 5 years; 16% (nâ =â 14) of infections had mixed strains. In the 70 children, approximately one-third of shared-strain infections were likely due to patient-to-patient transmission. Mixed-strain infections were associated with strain-sharing (odds ratio, 8.50; 95% confidence interval, 2.2-33.4; Pâ =â .002). Strain-sharing was not associated with antibiotic eradication treatment failure; however, nosocomial strain transmission was associated with establishment of chronic infection in a CF sibling pair. CONCLUSIONS: Although early P. aeruginosa CF infection is thought to reflect acquisition of diverse strains from community reservoirs, we identified frequent early CF strain-sharing that was associated with the presence of mixed strains and instances of possible patient-to-patient transmission.
Subject(s)
Cystic Fibrosis , Pseudomonas Infections , Anti-Bacterial Agents/therapeutic use , Child , Cystic Fibrosis/complications , Cystic Fibrosis/drug therapy , Humans , Pseudomonas Infections/drug therapy , Pseudomonas Infections/epidemiology , Pseudomonas aeruginosa/genetics , Retrospective StudiesABSTRACT
The lung clearance index (LCI) measured by the multiple breath washout (MBW) test is sensitive to early lung disease in children with cystic fibrosis. While LCI worsens during the preschool years in cystic fibrosis, there is limited evidence to clarify whether this continues during the early school age years, and whether the trajectory of disease progression as measured by LCI is modifiable.A cohort of children (healthy and cystic fibrosis) previously studied for 12â months as preschoolers were followed during school age (5-10â years). LCI was measured every 3â months for a period of 24â months using the Exhalyzer D MBW nitrogen washout device. Linear mixed effects regression was used to model changes in LCI over time.A total of 582 MBW measurements in 48 healthy subjects and 845 measurements in 64 cystic fibrosis subjects were available. The majority of children with cystic fibrosis had elevated LCI at the first preschool and first school age visits (57.8% (37 out of 64)), whereas all but six had normal forced expiratory volume in 1â s (FEV1) values at the first school age visit. During school age years, the course of disease was stable (-0.02â units·year-1 (95% CI -0.14-0.10). LCI measured during preschool years, as well as the rate of LCI change during this time period, were important determinants of LCI and FEV1, at school age.Preschool LCI was a major determinant of school age LCI; these findings further support that the preschool years are critical for early intervention strategies.
Subject(s)
Cystic Fibrosis , Breath Tests , Child , Child, Preschool , Disease Progression , Forced Expiratory Volume , Humans , Lung , Respiratory Function TestsABSTRACT
The treatment of lung infection in the context of cystic fibrosis (CF) is limited by a biofilm mode of growth of pathogenic organisms. When compared to planktonically grown bacteria, bacterial biofilms can survive extremely high levels of antimicrobials. Within the lung, bacterial biofilms are aggregates of microorganisms suspended in a matrix of self-secreted proteins within the sputum. These structures offer both physical protection from antibiotics as well as a heterogeneous population of metabolically and phenotypically distinct bacteria. The bacteria themselves and the components of the extracellular matrix, in addition to the signaling pathways that direct their behaviour, are all potential targets for therapeutic intervention discussed in this review. This review touches on the successes and failures of current anti-biofilm strategies, before looking at emerging therapies and the mechanisms by which it is hoped they will overcome current limitations.
Subject(s)
Anti-Bacterial Agents/pharmacology , Biofilms/drug effects , Cystic Fibrosis/microbiology , Lung Diseases/microbiology , Alginates/pharmacology , Anti-Bacterial Agents/administration & dosage , Bacteriophages , Cell Communication/drug effects , Cyclic GMP/analogs & derivatives , Cyclic GMP/metabolism , Cystic Fibrosis/complications , Humans , Iron/metabolism , Lung Diseases/drug therapy , Quorum Sensing/drug effectsABSTRACT
This report describes transmission of a Burkholderia cenocepacia ET12 strain (ET12-Bc) at the Toronto Adult Cystic Fibrosis (CF) Centre occurring from 2008 to 2017. Epidemiological and genomic data from 11 patients with CF were evaluated. Isolates were analysed using whole genome sequencing (WGS). Epidemiological investigation and WGS analysis suggested nosocomial transmission, despite enhanced infection control precautions. This was associated with subsequent deaths in 10 patients. ET12-Bc positive patients are no longer cared for on the same unit as ET12-Bc negative patients.
Subject(s)
Burkholderia Infections/transmission , Burkholderia cenocepacia/isolation & purification , Cystic Fibrosis , Adult , Bacterial Typing Techniques , Burkholderia Infections/epidemiology , Cross Infection/epidemiology , Cross Infection/microbiology , Humans , Ontario/epidemiologyABSTRACT
Cystic fibrosis (CF) lung infections caused by members of the Burkholderia cepacia complex, such as Burkholderia multivorans, are associated with high rates of mortality and morbidity. We performed a population genomics study of 111 B. multivorans sputum isolates from one CF patient through three stages of infection including an early incident isolate, deep sampling of a one-year period of chronic infection occurring weeks before a lung transplant, and deep sampling of a post-transplant infection. We reconstructed the evolutionary history of the population and used a lineage-controlled genome-wide association study (GWAS) approach to identify genetic variants associated with antibiotic resistance. We found the incident isolate was basally related to the rest of the strains and more susceptible to antibiotics from three classes (ß-lactams, aminoglycosides, quinolones). The chronic infection isolates diversified into multiple, distinct genetic lineages and showed reduced antimicrobial susceptibility to the same antibiotics. The post-transplant reinfection isolates derived from the same source as the incident isolate and were genetically distinct from the chronic isolates. They also had a level of susceptibility in between that of the incident and chronic isolates. We identified numerous examples of potential parallel pathoadaptation, in which multiple mutations were found in the same locus or even codon. The set of parallel pathoadaptive loci was enriched for functions associated with virulence and resistance. Our GWAS analysis identified statistical associations between a polymorphism in the ampD locus with resistance to ß-lactams, and polymorphisms in an araC transcriptional regulator and an outer membrane porin with resistance to both aminoglycosides and quinolones. Additionally, these three loci were independently mutated four, three and two times, respectively, providing further support for parallel pathoadaptation. Finally, we identified a minimum of 14 recombination events, and observed that loci carrying putative parallel pathoadaptations and polymorphisms statistically associated with ß-lactam resistance were over-represented in these recombinogenic regions.
Subject(s)
Burkholderia Infections/genetics , Burkholderia cepacia complex/genetics , Drug Resistance, Bacterial/genetics , Evolution, Molecular , Genes, Bacterial/genetics , Genetic Variation/drug effects , Genome-Wide Association Study , Humans , Recombination, GeneticABSTRACT
BACKGROUND: Nontuberculous mycobacteria are mycobacteria, other than those in the Mycobacterium tuberculosis complex, and are commonly found in the environment. Nontuberculous mycobacteria species (most commonly Mycobacterium avium complex and Mycobacterium abscessus) are isolated from the respiratory tract of approximately 5% to 40% of individuals with cystic fibrosis; they can cause lung disease in people with cystic fibrosis leading to more a rapid decline in lung function and even death in certain circumstances. Although there are guidelines for the antimicrobial treatment of nontuberculous mycobacteria lung disease, these recommendations are not specific for people with cystic fibrosis and it is not clear which antibiotic regimen may be the most effective in the treatment of these individuals. This is an update of a previous review. OBJECTIVES: The objective of our review was to compare antibiotic treatment to no antibiotic treatment, or to compare different combinations of antibiotic treatment, for nontuberculous mycobacteria lung infections in people with cystic fibrosis. The primary objective was to assess the effect of treatment on lung function and pulmonary exacerbations and to quantify adverse events. The secondary objectives were to assess treatment effects on the amount of bacteria in the sputum, quality of life, mortality, nutritional parameters, hospitalizations and use of oral antibiotics. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis Trials Register, compiled from electronic database searches and hand searching of journals and conference abstract books. Date of last search: 24 February 2020. We also searched a register of ongoing trials and the reference lists of relevant articles and reviews. Date of last search: 21 March 2019. SELECTION CRITERIA: Any randomized controlled trials comparing nontuberculous mycobacteria antibiotics to no antibiotic treatment, as well as one nontuberculous mycobacteria antibiotic regimen compared to another nontuberculous mycobacteria antibiotic regimen, in individuals with cystic fibrosis. DATA COLLECTION AND ANALYSIS: Data were not collected because in the one trial identified by the search, data specific to individuals with cystic fibrosis could not be obtained from the pharmaceutical company. MAIN RESULTS: One completed trial was identified by the searches, but data specific to individuals with cystic fibrosis could not be obtained from the pharmaceutical company. AUTHORS' CONCLUSIONS: This review did not find any evidence for the effectiveness of different antimicrobial treatment for nontuberculous mycobacteria lung disease in people with cystic fibrosis. Until such evidence becomes available, it is reasonable for clinicians to follow published clinical practice guidelines for the diagnosis and treatment of nodular or bronchiectatic pulmonary disease due to Mycobacterium avium complex or Mycobacterium abscessus in patients with cystic fibrosis.
Subject(s)
Anti-Bacterial Agents/therapeutic use , Cystic Fibrosis/microbiology , Lung Diseases/drug therapy , Mycobacterium Infections, Nontuberculous/drug therapy , Drug Therapy, Combination/methods , Humans , Lung Diseases/microbiology , Mycobacterium abscessus , Mycobacterium avium Complex , Nontuberculous MycobacteriaABSTRACT
BACKGROUND: Stenotrophomonas maltophilia is one of the most common emerging multi-drug resistant organisms found in the lungs of people with cystic fibrosis and its prevalence is increasing. Chronic infection with Stenotrophomonas maltophilia has recently been shown to be an independent predictor of pulmonary exacerbation requiring hospitalization and antibiotics. However, the role of antibiotic treatment of Stenotrophomonas maltophilia infection in people with cystic fibrosis is still unclear. This is an update of a previously published review. OBJECTIVES: The objective of our review is to assess the effectiveness of antibiotic treatment for Stenotrophomonas maltophilia in people with cystic fibrosis. The primary objective is to assess this in relation to lung function and pulmonary exacerbations in the setting of acute pulmonary exacerbations. The secondary objective is to assess this in relation to the eradication of Stenotrophomonas maltophilia. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis Trials Register, compiled from electronic database searches and handsearching of journals and conference abstract books. We also searched a registry of ongoing trials and the reference lists of relevant articles and reviews. Date of latest search: 03 March 2020. SELECTION CRITERIA: Randomized controlled trials of Stenotrophomonas maltophilia mono-infection or Stenotrophomonas maltophilia co-infection with Pseudomonas aeruginosa in either the setting of an acute pulmonary exacerbation or a chronic infection treated with suppressive antibiotic therapy. DATA COLLECTION AND ANALYSIS: Both authors independently assessed the trials identified by the search for potential inclusion in the review. MAIN RESULTS: We identified only one trial of antibiotic treatment of pulmonary exacerbations that included people with cystic fibrosis with Stenotrophomonas maltophilia. However, this trial had to be excluded because data was not available per pathogen. AUTHORS' CONCLUSIONS: This review did not identify any evidence regarding the effectiveness of antibiotic treatment for Stenotrophomonas maltophilia in people with cystic fibrosis. Until such evidence becomes available, clinicians need to use their clinical judgement as to whether or not to treat Stenotrophomonas maltophilia infection in people with cystic fibrosis. Randomized clinical trials are needed to address these unanswered clinical questions.
Subject(s)
Anti-Bacterial Agents/therapeutic use , Cystic Fibrosis/complications , Gram-Negative Bacterial Infections/drug therapy , Respiratory Tract Infections/drug therapy , Stenotrophomonas maltophilia , Cystic Fibrosis/microbiology , Gram-Negative Bacterial Infections/microbiology , Humans , Respiratory Tract Infections/microbiologyABSTRACT
BACKGROUND: Antibiotic therapy for acute pulmonary exacerbations in people with cystic fibrosis is usually chosen based on the results of antimicrobial susceptibility testing of individual drugs. Combination antimicrobial susceptibility testing assesses the efficacy of drug combinations including two or three antibiotics in vitro and can often demonstrate antimicrobial efficacy against bacterial isolates even when individual antibiotics have little or no effect. Therefore, choosing antibiotics based on combination antimicrobial susceptibility testing could potentially improve response to treatment in people with cystic fibrosis with acute exacerbations. This is an updated version of a previously published review. OBJECTIVES: To compare antibiotic therapy based on conventional antimicrobial susceptibility testing to antibiotic therapy based on combination antimicrobial susceptibility testing in the treatment of acute pulmonary exacerbations in people with cystic fibrosis and chronic infection with Pseudomonas aeruginosa. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Cystic Fibrosis Trials Register which comprises of references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings. Date of latest search: 19 March 2020. We also searched ongoing trials registries. Date of latest search: 07 April 2020. SELECTION CRITERIA: Randomised and quasi-randomised controlled studies of antibiotic therapy based on conventional antimicrobial susceptibility testing compared to antibiotic therapy based on combination antimicrobial susceptibility testing in the treatment of acute pulmonary exacerbations in cystic fibrosis due to chronic infection with Pseudomonas aeruginosa. DATA COLLECTION AND ANALYSIS: Both authors independently selected studies, assessed their quality and extracted data from eligible studies. Additionally, the authors contacted the study investigators to obtain further information. MAIN RESULTS: The search identified one multicentre study eligible for inclusion in the review. This study prospectively assessed whether the use of multiple combination bactericidal antibiotic testing improved clinical outcomes in participants with acute pulmonary exacerbations of cystic fibrosis who were infected with multiresistant bacteria. A total of 132 participants were randomised in the study. The study investigators provided data specific to the 82 participants who were only infected with Pseudomonas aeruginosa for their primary outcome of time until next pulmonary exacerbation. For participants specifically infected with only Pseudomonas aeruginosa, the hazard ratio of a subsequent exacerbation was 0.82, favouring the control group (95% confidence interval 0.44 to 1.51) (P = 0.52). No further data for any of this review's outcomes specific to participants infected with Pseudomonas aeruginosa were available. The risk of bias for the included study was deemed to be low. The quality of the evidence was moderate for the only outcome providing data solely for individuals with infection due to Pseudomonas aeruginosa. For other outcomes, we were unable to judge the quality of the evidence as no data were available for the relevant subset of participants. AUTHORS' CONCLUSIONS: The current evidence, limited to one study, shows that there is insufficient evidence to determine effect of choosing antibiotics based on combination antimicrobial susceptibility testing compared to choosing antibiotics based on conventional antimicrobial susceptibility testing in the treatment of acute pulmonary exacerbations in people with cystic fibrosis with chronic Pseudomonas aeruginosa infection. A large international and multicentre study is needed to further investigate this issue. The only study included in the review was published in 2005, and we have not identified any further relevant studies up to March 2017. We therefore do not plan to update this review until new studies are published.
Subject(s)
Anti-Bacterial Agents/therapeutic use , Cystic Fibrosis/microbiology , Pseudomonas Infections/drug therapy , Pseudomonas aeruginosa , Chronic Disease , Disease Progression , Drug Therapy, Combination , Humans , Microbial Sensitivity Tests , Pseudomonas aeruginosa/drug effects , Randomized Controlled Trials as TopicABSTRACT
BACKGROUND: Clinicians typically select the antibiotics used to treat pulmonary infections in people with cystic fibrosis based on the results of antimicrobial susceptibility testing performed on bacteria traditionally grown in a planktonic mode (grown in a liquid). However, there is considerable evidence to suggest that Pseudomonas aeruginosa actually grows in a biofilm (or slime layer) in the airways of people with cystic fibrosis with chronic pulmonary infections. Therefore, choosing antibiotics based on biofilm rather than conventional antimicrobial susceptibility testing could potentially improve response to treatment of Pseudomonas aeruginosa in people with cystic fibrosis. This is an update of a previously published Cochrane Review. OBJECTIVES: To compare biofilm antimicrobial susceptibility testing-driven therapy to conventional antimicrobial susceptibility testing-driven therapy in the treatment of Pseudomonas aeruginosa infection in people with cystic fibrosis. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis Trials Register, compiled from electronic database searches and handsearching of journals and conference abstract books. Most recent search: 07 April 2020. We also searched two ongoing trials registries and the reference lists of relevant articles and reviews. Most recent searches: 07 April 2020 and 05 September 2017. SELECTION CRITERIA: Randomized controlled trials (RCTs) of antibiotic therapy based on biofilm antimicrobial susceptibility testing compared to antibiotic therapy based on conventional antimicrobial susceptibility testing in the treatment of Pseudomonas aeruginosa pulmonary infection in people with cystic fibrosis. DATA COLLECTION AND ANALYSIS: Two authors independently selected RCTs, assessed their risk of bias and extracted data from eligible trials. Additionally, the review authors contacted the trial investigators to obtain further information. The quality of the evidence was assessed using the GRADE criteria. MAIN RESULTS: The searches identified two multicentre, double-blind RCTs eligible for inclusion in the review with a total of 78 participants (adults and children); one RCT was undertaken in people who were clinically stable, the second was in people experiencing pulmonary exacerbations. Both RCTs prospectively assessed whether the use of biofilm antimicrobial susceptibility testing improved microbiological and clinical outcomes in participants with cystic fibrosis who were infected with Pseudomonas aeruginosa. The primary outcome was the change in sputum Pseudomonas aeruginosa density from the beginning to the end of antibiotic therapy. Although the intervention was shown to be safe, the data from these two RCTs did not provide evidence that biofilm susceptibility testing was superior to conventional susceptibility testing either in terms of microbiological or lung function outcomes. One of the trials also measured risk and time to subsequent exacerbation as well as quality of life measures and did not demonstrate any difference between groups in these outcomes. Both RCTs had an overall low risk of bias and the quality of the evidence using GRADE criteria was deemed to be moderate to high for the outcomes selected. AUTHORS' CONCLUSIONS: The current evidence is insufficient to recommend choosing antibiotics based on biofilm antimicrobial susceptibility testing rather than conventional antimicrobial susceptibility testing in the treatment of Pseudomonas aeruginosa pulmonary infections in people with cystic fibrosis. Biofilm antimicrobial susceptibility testing may be more appropriate in the development of newer, more effective formulations of drugs which can then be tested in clinical trials.
Subject(s)
Anti-Bacterial Agents/therapeutic use , Biofilms/drug effects , Cystic Fibrosis/complications , Pseudomonas Infections/drug therapy , Pseudomonas aeruginosa/drug effects , Respiratory Tract Infections/drug therapy , Adolescent , Adult , Biofilms/growth & development , Female , Humans , Male , Microbial Sensitivity Tests/methods , Pseudomonas Infections/complications , Pseudomonas aeruginosa/physiology , Randomized Controlled Trials as Topic , Respiratory Tract Infections/microbiology , Sputum/microbiologyABSTRACT
Chronic lower airway infection with Pseudomonas aeruginosa is a major contributor to morbidity and mortality in individuals suffering from the genetic disease cystic fibrosis (CF). Whereas it was long presumed that each patient independently acquired unique strains of P. aeruginosa present in their living environment, multiple studies have since demonstrated that shared strains of P. aeruginosa exist among individuals with CF. Many of these shared strains, often referred to as clonal or epidemic strains, can be transmitted from one CF individual to another, potentially reaching epidemic status. Numerous epidemic P. aeruginosa strains have been described from different parts of the world and are often associated with an antibiotic-resistant phenotype. Importantly, infection with these strains often portends a worse prognosis than for infection with nonclonal strains, including an increased pulmonary exacerbation rate, exaggerated lung function decline, and progression to end-stage lung disease. This review describes the global epidemiology of clonal P. aeruginosa strains in CF and summarizes the current literature regarding the underlying biology and clinical impact of globally important CF clones. Mechanisms associated with patient-to-patient transmission are discussed, and best-evidence practices to prevent infections are highlighted. Preventing new infections with epidemic P. aeruginosa strains is of paramount importance in mitigating CF disease progression.
Subject(s)
Cystic Fibrosis/complications , Pseudomonas Infections/complications , Pseudomonas Infections/microbiology , Clone Cells , Cystic Fibrosis/microbiology , Humans , Prognosis , Pseudomonas Infections/epidemiology , Pseudomonas Infections/transmission , Pseudomonas aeruginosa/classificationABSTRACT
Median cystic fibrosis (CF) survival has increased dramatically over time due to several factors, including greater availability and use of antimicrobial therapies. During the progression of CF lung disease, however, the emergence of multidrug antimicrobial resistance can limit treatment effectiveness, threatening patient longevity. Current planktonic-based antimicrobial susceptibility testing lacks the ability to predict clinical response to antimicrobial treatment of chronic CF lung infections. There are numerous reasons for these limitations including bacterial phenotypic and genotypic diversity, polymicrobial interactions, and impaired antibiotic efficacy within the CF lung environment. The parallels to other chronic diseases such as non-CF bronchiectasis are discussed as well as research priorities for moving forward.